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A Aase

Publications and source records attributed to A Aase.

At least 37 records · Page 2Linked to original sources

Gender, geography and socio-economic status in the diffusion of malignant melanoma risk.

Malignant melanoma is the cancer that has shown the fastest increase in incidence in most white populations in recent decades. This paper studies the diffusion of the disease for males and females, geographical areas and socio-economic groups. Incidence data from the Norwegian Cancer Registry covering the period 1955-1989 make it possible to establish birth cohorts covering a time span from the late 1880s to the late 1950s. For Norway as a whole the increase in incidence was apparent between cohorts born in the 1880s and the 1890s for both sexes. The epidemic was first observable in the most central, south-eastern part of the country, with the onset reaching the most peripheral Northern Norway from the cohort born in the late 1910s. The onset also came later in rural than urban Norway. There are indications that the epidemic started in the more affluent part of the population, followed by an equalization. The increase in melanoma could be a result of more active outdoor recreation from the end of the last century. In cohorts born from the 1930s onwards a slowing down in the increase can be observed. International comparisons show that in most countries the incidence pattern in the first decades of the epidemic was dominated by males; later on the incidence became higher for females. Many cancer registries in the U.S.A. and Oceania now show a downward trend in melanoma incidence for males and females aged 15-29 years. A similar development has not been observed in Europe and Canada up to 1983-1987.

Adolescent↗

Incidence of malignant melanoma of the skin in Norway, 1955-1989: associations with solar ultraviolet radiation, income and holidays abroad.

BACKGROUND: Norway has the highest incidence of melanoma in Europe. This study analyses geographical variations in melanoma incidence within Norway and their association with possible aetiological factors. METHODS: Data on melanoma incidence from the Norwegian Cancer Registry were used to calculate standardized incidence ratios (SIR) for the 19 counties in Norway for each 5-year period from 1955 to 1989. Multiple regression analysis was used to examine the associations between these SIR and local UVB levels, holidays abroad and income. Similar methods were also used to analyse changes in SIR between 1955-1969 and 1985-1989. RESULTS: There was a highly significant association between melanoma incidence and UVB in each of the time periods studied. Income showed a significant positive association in the 1960s and early 1970s but not later. Foreign holidays showed a significant positive association in the 1980s, but not earlier. Changes in melanoma SIR between 1955-1969 and 1985-1989 were significantly positively associated with holidays abroad and negatively with income levels. CONCLUSIONS: Melanoma incidence in Norway is closely related to local levels of UVB radiation independently of other factors suggesting that local exposures carry significant risk. Risks would probably increase if ozone depletion led to enhanced UVB flux (estimated as 1.6% rise in incidence for each 1% increase in UVB). By the end of the study period income was no longer a significant factor but holidays abroad had started to have a detectable effect on melanoma incidence.

Environmental Exposure↗

Comparison among opsonic activity, antimeningococcal immunoglobulin G response, and serum bactericidal activity against meningococci in sera from vaccinees after immunization with a serogroup B outer membrane vesicle vaccine.

Opsonic activity in sera from 27 military recruits vaccinated with the Norwegian meningococcal serogroup B outer membrane vesicle vaccine was measured as respiratory burst with polymorphonuclear leukocytes as the effector cells and meningococci of the epidemic strain as the target. The results were compared with antimeningococcal IgG antibodies against an outer membrane vesicle coat in an enzyme-linked immunosorbent assay and with serum bactericidal activity. The vaccinees were immunized twice, with a 6-week interval between the two. The serum samples studied were collected at day zero, after 6 weeks, and after 12 weeks. Both serum bactericidal activity and respiratory burst were measured by adding external serum as the complement source. The results revealed a significant increase in specific IgG response, serum bactericidal activity, and respiratory burst after vaccination. We found a highly significant correlation between the responses in all three assays (P < 0.0001). The highest correlation was found between respiratory burst and antimeningococcal IgG response (r = 0.93). This result strongly indicates that respiratory burst is mediated almost exclusively by IgG antibodies. The correlation between antimeningococcal IgG response and serum bactericidal activity was slightly lower (r = 0.83). The correlation between respiratory burst and serum bactericidal activity was further reduced (r = 0.78), and some of the sera revealed a marked preference for only one of the activities. This result means that respiratory burst and serum bactericidal activity in part are induced by different mediators, and to obtain a more complete picture of the potential protective activity, both assays should be applied to survey a vaccine trial.

Adult↗

Ischaemic heart disease mortality among men in Norway: reversal of urban-rural difference between 1966 and 1989.

OBJECTIVE: This study aimed to examine regional urban-rural differences in mortality from ischaemic heart disease, including sudden death of unknown cause (IHD/SUD) in Norway from 1966-89, for men and women aged 30-69 years. DESIGN: Analysis was based on vital statistics. Regional mortality rates were obtained by aggregating the 443 municipalities in Norway into urban, rural, and intermediate municipalities. SETTINGS AND SUBJECTS: Norway. RESULTS: In 1966-70 the age adjusted IHD/SUD mortality in the age group 30-69 years was higher in urban than in rural areas; for men by 31% (95% CI 27%, 36%) and for women by 28% (95% CI 19%, 36%). In 1986-89 the IHD/SUD mortality for men showed a reversed urban-rural gradient: it was 8% (95% CI 2%, 13%) higher in rural than in urban areas. The mortality rates for women were equal for both these aggregates. For men the results indicate that IHD/SUD mortality peaked first in urban municipalities and then, but at a lower level, in rural areas. For women there was a substantial decline in IHD/SUD mortality between 1966 and 1989, but an actual peak could not be demonstrated in any of the three aggregates during the period. The decline in IHD/SUD mortality among women was steepest in urban municipalities and least noticeable in rural municipalities, but the decline tapered off towards the end of the study period. CONCLUSION: The results confirm a phase-shifted peak in IHD/SUD mortality, which began in towns and ended in rural areas, and provides clues to the main underlying factors in the IHD epidemic at the population level.

Adult↗

One disulfide bond in front of the second heavy chain constant region is necessary and sufficient for effector functions of human IgG3 without a genetic hinge.

We have created four IgG3 mutants without a normal hinge region: (i) m0 without a genetic hinge; (ii) m0/C131S, where Cys-131 in m0 was mutated to Ser; (iii) m0/231C232 (formerly HM-1), where a Cys residue was inserted in m0 between Ala-231 and Pro-232; (iv) m0/C131S/231C232, which is a hybrid of m0/231C232 and m0/C131S. The wild-type IgG3 and all mutants bind 5-iodo-4-hydroxy-3-nitrophenacetyl groups. The wild type and mutants, m15 (with 15 aa in the hinge), m0/231C232, and m0/C131S/231C232, were all positive for complement-mediated lysis, antibody-dependent cellular cytotoxicity mediated by peripheral blood leukocytes, and phagocytosis by U937. m0/C131S/231C232 was only weakly positive and sometimes negative for respiratory burst activity mediated by peripheral blood neutrophils (polymorphonuclear leukocytes), whereas m15, m0/231C232, and wild-type IgG3 were strongly positive. The m0 and m0/C131S mutants were mainly negative for complement-mediated lysis, antibody-dependent cell-mediated cytotoxicity, and phagocytosis by U937 and polymorphonuclear leukocytes. The results indicate that a hinge spacer region is not necessary, but the correct alignment of the two second heavy chain constant regions in the IgG3 molecule by a minimum of one disulfide bond is necessary and sufficient for effector functions.

Amino Acid Sequence↗

Human IgG isotype-specific amino acid residues affecting complement-mediated cell lysis and phagocytosis.

In this report we describe the construction of anti-5-iodo-4-hydroxy-3-nitrophenacetyl (NIP) mouse/human immunoglobulin (Ig) G4 chimeric molecules with altered amino acid residues in the CH2 domain. Three mutants are described. Gln-268 is substituted by His in gamma 4 Q268H, Ser-331 is substituted by Pro in gamma 4 S331P, and in gamma 4 Q268H/S331P both residues are substituted. The ability of the mutant molecules to induce complement-mediated cell lysis (CML) and phagocytosis by Fc gamma RII- and Fc gamma RIII-bearing polymorphonuclear leukocytes (PMN) were measured. In CML, gamma 4 Q268H was inactive, but both gamma 4 S331P and gamma 4 Q268H/S331P were active provided that the antigenic density on the target cells was high. In phagocytosis mediated by PMN, the mutants gamma 4 S331P and gamma 4 Q268H/S331P were both active only when complement was introduced. gamma 4 Q268H was not active in phagocytosis under any conditions. We conclude that His-268 in human IgG molecules does not modulate CML activity or phagocytosis mediated by Fc gamma RII and/or Fc gamma RIII. Pro-331 rescues CML activity in IgG4 molecules when the epitope density on the target cells is high, but does not affect Fc gamma RII/Fc gamma RIII-mediated phagocytosis. In this manner the mutants gamma 4 S331P and gamma 4 Q268H/S331P mimic human IgG2. This could indicate a structural similarity between IgG2 and these mutant molecules that distinguish them from both IgG1 and IgG3.

Animals↗

Opsonophagocytic activity induced by chimeric antibodies of the four human IgG subclasses with or without help from complement.

The opsonophagocytic activity of the four human IgG subclasses was studied using chimeric mouse-human antibodies with specificity for the hapten NIP. As target cells we used haptenized sheep red blood cells and N. meningitidis, labelled with different amounts of hapten. We used polymorphonuclear leucocytes (PMN) as effector cells to measure respiratory burst (RB), and U937 to measure phagocytosis/rosette formation. When the target cells were opsonized with antibody only, and PMN used as effector cells, IgG3 was highly efficient, while IgG1 revealed an intermediate activity and IgG2 and IgG4 were negative. The same pattern among the subclasses was obtained in the presence of complement source, when target cells with low hapten concentration were used. However, at high epitope concentration on the target cells, in the presence of complement source, IgG2 was highly active, while IgG4 was still negative or only slightly positive. When U937 were used as effector cells and complement was omitted, IgG1, IgG3 and IgG4 all revealed high phagocytic/rosette-forming activity, while IgG2 was negative. When the target cells were opsonized with antibody and complement, the phagocytic/rosette-forming activity was often suppressed. Our results reveal that all four human IgG subclasses possess opsonophagocytic capacity, but with different requirements concerning complement and Fc gamma Rs. They also enlighten us as to how IgG2 might perform its protective effect against harmful bacteria displaying high density of carbohydrate epitopes on their outside surface.

Animals↗

The extended hinge region of IgG3 is not required for high phagocytic capacity mediated by Fc gamma receptors, but the heavy chains must be disulfide bonded.

Fc gamma receptor (Fc gamma R) phagocytosis and respiratory burst were induced by chimeric mouse-human anti-(4-hydroxy-5-iodo-3-nitrophenyl) acetyl IgG3 antibodies with mutations in hinge and/or in CH1 region. IgG3 mutants with different hinge length ranging from 47 to 0 amino acids, an IgG3 molecule with an artificial hinge of just one cysteine residue (HM-1), and two hybrid IgG3 molecules with IgG4 hinge or IgG4 CH1-hinge were tested. Using the monocytic cell line U937 as effector cells, the mutated IgG3 molecules were very similar, revealing high activity, while the IgG3/IgG4 hybrids revealed a slightly reduced activity. However, the hingeless (0-h) mutant was negative, except after interferon-gamma stimulation when it became slightly positive. Interestingly, HM-1 was as active as the IgG3 mutants. With polymorphonuclear leucocytes (PMN) as effector cells we obtained some day-to-day variations, but all the IgG3 mutants were highly active, with the two shortest hinge mutants somewhat less active. The IgG3/IgG4 hybrid molecules revealed an intermediate activity, while IgG4 wild-type and the 0-h mutant were negative. However, the HM-1 molecule revealed an activity similar to that of the IgG3 mutants. The phagocytic activity of U937 was inhibited by monomeric IgG, indicating the importance of Fc gamma RI. In contrast, with PMN both blockage of Fc gamma RII and cleavage of Fc gamma RIII were required to significantly reduce the phagocytosis and respiratory burst, thus showing that both receptors contribute to the effect. These results demonstrate that the extended IgG3 hinge region is not necessary for a high phagocytic activity and that the major structural importance of the hinge is to connect the two heavy chains in this region.

Disulfides↗

Human IgG3 can adopt the disulfide bond pattern characteristic for IgG1 without resembling it in complement mediated cell lysis.

In this paper we describe the construction of mouse-human IgG3 mutant antibodies resembling IgG1 in their disulfide bond pattern between the heavy and light chain (H-L) and between the two heavy chains (H-H). The effector functions of these mutant antibodies were compared to normal IgG3 and IgG1. Changing only the disulfide bond pattern between the heavy and light chains did not alter the ability to induce complement mediated cell lysis (CML), regardless of the amount of corresponding antigen that had been introduced to the surface of the target cells. However, alteration of the disulfide bond pattern between the two heavy chains had a large effect on CML due to shortening of the hinge from 62 to 15 amino acids. No difference between the mutants and normal antibodies in antibody-dependent cell-mediated cytotoxicity (ADCC) was observed. This suggests that IgG3 can adopt the H-L disulfide bond pattern of IgG1 without obtaining the CML activity characteristic for IgG1.

Amino Acid Sequence↗

Human IgG3 is decreased and IgG1, IgG2 and IgG4 are unchanged in molecular size by mild reduction and reoxidation without any major change in effector functions.

Purified proteins of the four human IgG subclasses were reduced under neutral conditions to break the interchain S-S bonds, followed by dialysis to allow reformation of S-S bonds (pr/o treatment). The IgG1, IgG2 and IgG4 proteins apparently reformed native molecules by pr/o treatment, while IgG3 formed molecules with significantly smaller size, as measured by HPLC gel filtration, compared to the autologous native proteins. The degree of shrinking of the pr/o IgG3 molecules varied and was most pronounced at low protein concn. In addition, the temp and the concn of reducing agent during the pr/o treatment had some influence on the molecular size. The effect is probably due to a conformational change of the 62 amino acid long hinge of IgG3. The effector activity of pr/o IgG2 and pr/o IgG3 was studied by employing chimeric, mouse V and human C regions, monoclonal antibodies with the same NIP-binding properties. Thus, the interaction between IgG and the complement system was unchanged both for pr/o IgG2 and pr/o IgG3, while the Fc-receptor-mediated antibody-dependent cellular cytotoxicity (ADCC) was depressed to the same degree for both pr/o IgG2 and pr/o IgG3. Conclusively, the alteration of the conformation of the IgG3 molecule by pr/o treatment had no major influence on its effector functions.

Animals↗

Unexpected interaction of some anti-TNP hybridoma antibodies with Superose HPLC gel filtration resins.

Five different hybridoma antibodies (the isotypes IgG1, IgG2a and IgG2b), reactive with TNP, showed increased elution times when gel filtered on a Superose-12 HPLC column corresponding to apparent molecular weights ranging from 54 kDa to 120 kDa compared to the normal of 150 kDa. One of the antibodies (C1901-B4) was studied in detail showing that the unusual gel filtration behaviour was localized to the Fab part of the molecule. SDS-PAGE analysis showed that the intact antibodies had normal molecular weights. Gel filtration on a Toyosoda G-3000SW HPLC column and Sephadex G-150 as well as Sepharose 6B generally showed normal elution times. These results support the hypothesis that the retardation on the Superose gel is probably due to aromatic interactions between amino acid residues supposedly exposed in the hypervariable region (i.e., the antibody combining site) of the antibody, and the gel matrix which is rich in ether O-atoms created during the manufacturing process. If this hypothesis is correct one might expect such interactions between Superose resins and antibodies of many different specificities in which aromatic amino acids are exposed in the combining sites.

Chromatography, Gel↗

Antibody dependent cell-mediated cytotoxicity induced by chimeric mouse-human IgG subclasses and IgG3 antibodies with altered hinge region.

A matched set of chimeric mouse-human NP-antibodies were studied for the capacity to induce cell mediated cytotoxicity (ADCC) by normal peripheral blood NK/K cells. The target cells were sheep red blood cells (SRBC) sensitized with the haptens NP or NIP. All four IgG subclasses and several IgG3 variants with altered hinge were tested for ADCC activity. The hierarchy of the ADCC capacity among the subclasses was found to be IgG3 greater than IgG1 greater than IgG4 greater than IgG2. The superiority of IgG3 was only revealed at low effector cell:target cell ratio. The ADCC activity was for the most part unaltered by shortening the hinge region of IgG3 from 62 to 15 amino acids. Also, when the hinge region of IgG3 was mutated to become identical to that of IgG4, the ADCC activity was mainly unchanged. However, an IgG3 variant with deletion of all four hinge exons showed a depressed ADCC activity compared to the wild type. The IgG subclass pattern of complement-mediated lysis (CML) and ADCC is different and the capacity to induce CML and ADCC is changed differently by hinge region modification. Thus CML and ADCC have different structural requirements in the Fc region of IgG.

Amino Acid Sequence↗

The changing geography of mortality in Norway, 1969-1989.

"Changes in the geographical mortality pattern for Norway between 1969 and 1989 are explored for total mortality, coronary heart disease, stomach cancer, breast cancer, lung cancer, melanoma, infant mortality and suicide. The period has shown considerable flux. Coronary heart disease mortality used to be higher in urban than rural areas, but the situation has now reversed (for men) or equalized (for women). The excess infant mortality in the periphery has been eliminated. Suicide has increased faster in fishing and farming areas than in the cities. The changes are interpreted through some concepts and models: the epidemiological transition, geographical and social diffusion, regional restructuring, changes of the physical environment and geographical uniqueness." Data are from official sources.

Biology↗

The use of a hapten-Fab conjugate to sensitize target cells for antibody-dependent complement-mediated lysis and antibody-dependent cell-mediated cytotoxicity.

NIP-conjugated Fab' fragments from a rabbit hyperimmunized with sheep red blood cells (SRBC) were used to link the hapten NIP to target cells for antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent complement-mediated lysis (ADCML). Target cells (SRBC) labelled with this NIP-Fab' complex were compared with SRBC directly haptenized with NIP in ADCC and ADCML assays using a NIP specific IgG1 chimeric antibody. Both methods yielded almost identical results. Using the NIP-FAb' conjugate identical target cell haptenization was readily achieved from experiment to experiment. Using conjugates of different NIP/Fab' ratios it should be possible to study how such changes influence antibody effector functions.

Animals↗

Human IgG subclass pattern of inducing complement-mediated cytolysis depends on antigen concentration and to a lesser extent on epitope patchiness, antibody affinity and complement concentration.

The relative complement-mediated lytic capability of the IgG subclass isotypes was studied using a matched set of mouse-human chimeric anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) antibodies. The subclass pattern was shown to be highly dependent on variations in antigen concentration and to lesser extent on variation in epitope patchiness, antibody binding affinity and complement concentration. In general, the IgG3 subclass was most effective in inducing cytolysis at the different conditions used and only at high antigen concentration did the IgG1 subclass mediated more efficient cytolysis than IgG3. The IgG2 isotype required a relative high antigen concentration to be cytolytic while the IgG4 isotype was not cytolytic at any of the conditions tested. These individual characters of each of the IgG subclasses makes it conceivable that a subtle system of immunoregulation exists among the subclasses.

Antibody Affinity↗

Chimeric mouse human IgG3 antibodies with an IgG4-like hinge region induce complement-mediated lysis more efficiently than IgG3 with normal hinge.

We have altered the amino acid sequence of the hinge and the first constant domain (CH1) of mouse/human chimeric IgG3 antibodies by site-directed mutagenesis, so as to make the sequences identical to those of IgG4. All the mutant antibodies with altered hinge region were more active in complement activation and complement-mediated lysis than native IgG3. The mutations in CH1, however, did not alter the activity. This demonstrates the importance of the hinge region in modulating this effector function. The results show that the primary structure of neither CH1 nor the hinge of IgG4 is responsible for the lack of complement activation shown by this subclass.

Amino Acid Sequence↗

C3, C4, and the terminal complement complex differ from C1q by binding predominantly to the antigenic part of solid phase immune complexes.

The binding of the C components C1q, C4, C3, the terminal C5b-9 complement complex (TCC) and S protein to immune complexes was studied. The hapten 5-iodo-4-hydroxy-3-nitrophenacetyl (NIP) conjugated to BSA was adsorbed to polystyrene plates and reacted with a human IgG3-mouse chimeric anti-NIP antibody. After addition of serum a dose-dependent binding of C1q, C4, C3, and TCC to the immune complexes was found. An increase in the amount of NIP-BSA was associated with an increase in the binding of TCC and a decrease in the binding of S-protein. After addition of soluble NIP only 4 to 6% of the anti-NIP antibody remained bound to the Ag. C1q showed diminished binding after addition of NIP, whereas C4, C3, and TCC quantitatively remained bound to the Ag. Binding of TCC to the immune complexes was also found in an alternative assay, in which the anti-NIP antibody was adsorbed to the solid phase before NIP-BSA and an additional layer of anti-NIP antibody were added. The supernatants from the solid phase assay were tested for C3 activation and formation of the fluid phase TCC (SC5b-9). Activation of the C3 was reflected in the fluid phase by a dose-dependent increase in C3 activation products. This was not seen for TCC despite increased binding to the solid phase.

Animals↗

Enhancement of complement activation and cytolysis of human IgG3 by deletion of hinge exons.

The capacity to induce complement-mediated cell lysis is greatly enhanced by truncating the hinge of IgG3 through exon deletions. This was shown by establishing five new cell lines which secreted chimeric IgG3 molecules with specificity for the hapten 4-hydroxy-3-nitrophenacetyl (NP) and having 47,45,32,15, and 0 amino acid hinge regions (the wild-type IgG3 has 62 amino acids in the hinge). Efficient complement activation and complement-mediated cell lysis did not depend on a long total hinge or on a long 'upper' hinge (the stretch from the beginning of the hinge to the first inter-heavy chain S-S bond). On the contrary, the mutant having a 15 amino acid hinge element was up to 10 times more efficient in complement lysis than the wild type. Thus the complement-activation potential appeared to be down-regulated in the wild type. On the other hand, the mutant lacking the hinge altogether did not activate complement or induce complement-mediated cytolysis. These findings have to be taken into account when antibodies are designed for human therapy.

Antibody Affinity↗